Piperidines

ABSTRACT

Compounds, compositions and methods are provided which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-dependent sodium channels. More particularly, the invention provides substituted piperidines, and compositions containing these compounds. Also provided are methods using the compounds of the invention for the treatment of central or peripheral nervous system disorders, particularly pain and chronic pain by blocking sodium channels associated with the onset or recurrance of the indicated conditions. The compounds, compositions and methods of the present invention are of particular use for treating neuropathic or inflammatory pain by the inhibition of ion flux through a channel that includes a PN3 subunit.

CROSS-REFERENCES TO RELATED APPLICATIONS

This is a non-provisional filing of U.S. Provisional Patent Application No. 60/335,930, filed on Nov. 1, 2001, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

This invention relates to the use of certain piperidine compounds as sodium channel inhibitors and to the treatment of neuropathic pain by the inhibition of sodium channels. Additionally, this invention relates to novel piperidine-based compounds that are useful as sodium channel inhibitors.

BACKGROUND OF THE INVENTION

Sodium channel-blocking agents have been reported to be effective in the treatment of various disease states, and have found particular use as local anesthetics and in the treatment of cardiac arrhythmias. It has also been reported that sodium channel-blocking agents may also be useful in the treatment of pain, including neuropathic pain; see, for example, Tanelian et al. Pain Forum. 4(2), 75-80 (1995). Preclinical evidence demonstrates that sodium channel-blocking agents selectively suppress abnormal ectopic neural firing in injured peripheral and central neurons, and it is via this mechanism that they are believed to be useful for relieving pain. Consistent with this hypothesis, it has been shown that sodium channels accumulate in the peripheral nerve at sites of axonal injury (Devor et al. J. Neurosci. 132: 1976 (1993)). Alterations in either the level of expression or distribution of sodium channels within an injured nerve, therefore, have a major influence on the pathophysiology of pain associated with this type of trauma.

An increasing body of evidence suggests that a voltage-dependent, tetrodotoxin (TTX)-resistant Na channel, PN3 (Na_(v)1.8), may play a key role in sensitization in neuropathic pain states. Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. Clinical manifestations of neuropathic pain include a sensation of burning or electric shock, feelings of bodily distortion, allodynia and hyperalgesia.

PN3 is a member of a family of voltage-gated sodium channel alpha subunits. Names for this family include SCN, SCNA, and Na_(v)x.x. There are currently 10 known members falling into two subfamilies Na_(v)1 (all but SCN6A) and Na_(v)2 (SCN6A). The human channel was cloned by Rabert et al. (Pain 78(2): 107-114 (1998)). PN3 of other species has also been cloned. See, for example, Chen et al., Gene 202(1-2), 7-14 (1997); Souslova et al., Genomics 41(2), 201-209 (1997); Akopian et al., Nature 379(6562), 257-262 (1996).

PN3-null mutant mice exhibit a pronounced analgesia to mechanical noxious stimuli (Akopian A. N. et al., Nature Neurosci., 2(6): 541-548 (1999)). Selective “knock down” of PN3 protein in the rat dorsal root ganglion with specific antisense oligodeoxynucleotides prevents hyperalgesia and allodynia caused by either chronic nerve or tissue injury (Porreca et al., Proc. Nat. Acad. Sci., USA, 96: 7640-7644 (1999)). The biophysical properties of PN3 make it ideally suited to sustain repetitive firing of sensory neurons at the depolarized potentials characteristic of injured peripheral nerves. In both human and animal models of neuropathic pain, there is an increased expression of PN3 at the site of peripheral nerve injury (Clare et al., DDT 5: 506-519 (2000); Coward et al., Pain 85: 41-50 (2000)).

Patients with neuropathic pain do not respond to non-steroidal anti-inflammatory drugs (NSAIDS) and resistance or insensitivity to opiates is common. Most other treatments have limited efficacy or undesirable side effects. Mannion et al., Lancet, 353: 1959-1964 (1999) from the Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School wrote: “There is no treatment to prevent the development of neuropathic pain, nor to adequately, predictably and specifically control established neuropathic pain.”

PN3 is a promising molecular target for the treatment of neuropathic pain. One of the most attractive features of PN3 is the highly restricted and peripheral nature of its expression. Antisense studies have revealed no overt (particularly CNS-related) adverse effects, consistent with the localized, peripheral distribution of the channel (Novakovic et al., J. Neurosci., 18(6): 2174-2187 (1998)). Additionally, the high activation threshold of PN3 suggests that the channel may be relatively uninvolved in normal nociception. These properties of PN3 present the possibility that selective blockade of this particular voltage-gated sodium channel (VGSC) may offer effective pain relief without the significant side effect liability normally associated with more promiscuous VGSC blocking drugs. The compounds of the invention are potent inhibitors of PN3 channels.

Ohkawa et al. have described a class of cyclic ethers that are of use as sodium channel blockers (U.S. Pat. No. 6,172,085).

Currently, gabapentin is the market leading treatment for neuropathic pain. As with epilepsy, its mechanism of action for pain is unknown. It is a very safe, easy to use drug, which contributes to its sales. Efficacy for neuropathic pain is not impressive, as few as only 30% of patients respond to gabapentin treatment. Carbamazepine is also used to treat neuropathic pain.

In view of the limited number of agents presently available and the low levels of efficacy of the available agents, there is a pressing need for compounds that are potent, specific inhibitors of ion channels implicated in neuropathic pain. The present invention provides such compounds, methods of using them, and compositions that include the compounds.

SUMMARY OF THE INVENTION

It has now been discovered that piperidines are potent inhibitors of sodium channels. In the discussion that follows, the invention is exemplified by reference to the inhibition of sodium channels that are localized in the peripheral nervous system, and in particular those inhibitors that are selective inhibitors of PN3, and are useful for treating neuropathic pain through the inhibition of sodium ion flux through channels that include the PN3 subunit. The focus of the discussion is for clarity of illustration only.

The compounds and methods of the present invention are useful for treating diseases in which blocking or inhibiting one or more PN3 ion channel provides relief from the disease. Of particular interest is the use of the compounds and methods of the invention for treating pain and central or peripheral nervous system disorders. The present invention is of use for treating both inflammatory and neuropathic pain.

The present invention provides compounds which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-dependent sodium channels. More particularly, the invention provides compounds, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders, particularly pain and chronic pain.

In one aspect, the present invention provides compounds according to Formula I:

In Formula I, R¹ represents a moiety is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubsituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl,

The symbol R² represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, alkoxy, or —NR¹⁵R¹⁶. R¹⁵ and R¹⁶ are each members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl and R¹⁵ and R¹⁶ taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic ring.

R³ is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and NR¹⁵R¹⁶. R⁴ is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, and NR¹⁵R¹⁶. R⁵ is a member selected from H, nitro, substituted or unsubstituted alkyl, cyano, acyl, and SO₂R¹¹. R¹¹ is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

Y is a member selected from O, C—NO₂ and S. Z is a member selected from:

in which A, D, E and M are independently selected from CR¹², N, and N-oxide. R¹² is a member selected from hydrogen, halo, amino, hydroxy, cyano, nitro, acyl, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, and at least two of A, D, E and M is a selected from CR¹², and at most one of A, D, E, and M is N-oxide. X is a member selected from O, C—NO₂, S and NR¹⁰.

R⁶, R⁷ and R⁸ are members independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aminoalkyl, and R⁷ and R⁸ together with the atom to which they are joined are optionally joined to form a 4- to 8-membered heterocycloalkyl ring.

R⁹ is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted and unsubstituted heterocycloalkyl, OR²⁰, and SR²⁰. R²⁰ is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and substituted and unsubstituted heterocycloalkyl.

R¹⁰ is a member selected from hydrogen cyano, nitro, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted and unsubstituted heteroaryl and SO₂R¹¹.

The dashed bond marked a is either a single or a double bond; and n is and integer selected from 0, 1, and 2.

In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound provided above.

In yet another aspect, the present invention provides a method for inhibition of ion flux through voltage dependent sodium channels, comprising contacting a cell containing the target ion channels with a compound of the formula provided above.

In still another aspect, the present invention provides a method for the treatment of diseases through inhibition of ion flux through voltage dependent sodium channels, the method comprising treating the host with an effective amount of a sodium channel inhibiting compound of the formula provided above.

Other objects, advantages and embodiments of the invention will be apparent from review of the detailed description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 displays structures of representative compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

Abbreviations and Definitions:

The abbreviations used herein have their conventional meaning within the chemical and biological arts. For example: CHO, Chinese hamster ovary; EBSS, Earl's Balanced Salt Solution; SDS, sodium dodecyl sulfate; Et₃N, triethylamine; MeOH, methanol; and DMSO, dimethylsulfoxide.

The term “pain” refers to all categories of pain, including pain that is described in terms of stimulus or nerve response, e.g., somatic pain (normal nerve response to a noxious stimulus) and neuropathic pain (abnormal response of a injured or altered sensory pathway, often without clear noxious input); pain that is categorized temporally, e.g., chronic pain and acute pain; pain that is categorized in terms of its severity, e.g., mild, moderate, or severe; and pain that is a symptom or a result of a disease state or syndrome, e.g., inflammatory pain, cancer pain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiac ischaemia, and diabetic neuropathy (see, e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991); Williams et al., J. of Medicinal Chem. 42:1481-1485 (1999), herein each incorporated by reference in their entirety).

“Somatic” pain, as described above, refers to a normal nerve response to a noxious stimulus such as injury or illness, e.g., trauma, burn, infection, inflammation, or disease process such as cancer, and includes both cutaneous pain (e.g., skin, muscle or joint derived) and visceral pain (e.g., organ derived).

“Neuropathic” pain, as described above, refers to pain resulting from injury to or chronic changes in peripheral and/or central sensory pathways, where the pain often occurs or persists without an obvious noxious input.

“Biological medium,” as used herein refers to both in vitro and in vivo biological milieus. Exemplary in vitro “biological media” include, but are not limited to, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.

“Compound of the invention,” as used herein refers to the compounds discussed herein, pharmaceutically acceptable salts and prodrugs of these compounds.

“Inhibiting” and “blocking,” are used interchangeably herein to refer to the partial or full blockade of a PN3 channel by a compound of the invention, which leads to a decrease in ion flux either into or out of a cell in which a PN3 channel is found.

Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents which would result from writing the structure from right to left, e.g., —CH₂O— is intended to also recite —OCH₂—; —NHS(O)₂— is also intended to represent. —S(O)₂HN—, etc.

The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C₁-C₁₀ means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “alkyl,” unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl.” Alkyl groups, which are limited to hydrocarbon groups are termed “homoalkyl”.

The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by —CH₂CH₂CH₂CH₂—, and further includes those groups described below as “heteroalkylene.” Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom selected from O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—H₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the term “heteroalkylene” by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—.

In general, an “acyl substituent” is also selected from the group set forth above. As used herein, the term “acyl substituent” refers to groups attached to, and fulfilling the valence of a carbonyl carbon that is either directly or indirectly attached to the polycyclic nucleus of the compounds of the present invention.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C₁-C₄)alkyl” is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term “arylalkyl” is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and “heteroaryl”) include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Substituents for the alkyl, and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generally referred to as “alkyl substituents” and “heteroalkyl substituents,” respectively, and they can be one or more of a variety of groups selected from, but not limited to: -hydrogen, —OR′, ═O, ═NR″″, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR′C(O)R″, —NR′″—C(O)NR′R″, —NR′C(O)₂R″, —NR′″—C(NR′R″)═NR″″, —NR′″—C(NR′R″)═NR″″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′SO₂R″, —NR′″SO₂NR′R″—CN, —R′ and —NO₂ in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. R′, R″, R′″ each preferably independently refer to hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, (e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups), substituted or unsubstituted heteroaryl and substituted or unsubstituted arylalkyl. R″″ refers to hydrogen, alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, —CN, —NO₂ and —S(O)₂R′. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″ and R″″ groups when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical, the aryl substituents and heteroaryl substituents are generally referred to as “aryl substituents” and “heteroaryl substituents,” respectively and are varied and selected from, for example: hydrogen, —OR′, —C═NR″″NR′R″, —NR′″SO₂NR′R″, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′″—C(O)NR′R″, —NR″C(O)₂R′, —NR′″—C(NR′R″)═NR″″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR″SO₂R′, —CN and —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R″ and R′″ each preferably independently refer to hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, (e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups), substituted or unsubstituted heteroaryl and substituted or unsubstituted arylalkyl. R″″ refers to hydrogen, alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, —CN, —NO₂ and —S(O)₂R′. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″ and R″″ groups when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl and 4-morpholinyl.

Two of the aryl substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—, —CRR′— or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —A—(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substituents R, R′, R″ and R′″ are preferably independently selected from hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

The symbol “R” is a general abbreviation that represents a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl groups.

The term “pharmaceutically acceptable salts” includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

Description of the Embodiments

I. Inhibitors of Voltage-Dependent Sodium Channels

In one aspect, the present invention provides compounds according to Formula I:

In Formula I, R¹ represents a moiety is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubsituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl,

The symbol R² represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, alkoxy, or —NR¹⁵R¹⁶. R¹⁵ and R¹⁶ are each members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl and R¹⁵ and R¹⁶ taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic ring.

R³ is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and NR¹⁵R¹⁶R⁴ is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, and NR¹⁵R¹⁶. R⁵ is a member selected from H, nitro, substituted or unsubstituted alkyl, cyano, acyl, and SO₂R¹¹. R¹¹ is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

Y is a member selected from O, C—NO₂ and S. Z is a member selected from:

in which A, D, E and M are independently selected from CR¹², N, and N-oxide. R¹² is a member selected from hydrogen, halo, amino, hydroxy, cyano, nitro, acyl, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, and at least two of A, D, E and M is a selected from CR¹², and at most one of A, D, E, and M is N-oxide. X is a member selected from O, C—NO₂, S and NR¹⁰.

R⁶, R⁷ and R⁸ are members independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aminoalkyl, and R⁷ and R⁸ together with the atom to which they are joined are optionally joined to form a 4- to 8-membered heterocycloalkyl ring.

R⁹ is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted and unsubstituted heterocycloalkyl, OR²⁰, and SR²⁰. R²⁰ is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and substituted and unsubstituted heterocycloalkyl.

R¹⁰ is a member selected from hydrogen cyano, nitro, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted and unsubstituted heteroaryl and SO₂R¹¹.

The dashed bond marked a is either a single or a double bond; and n is and integer selected from 0, 1, and 2.

In a preferred embodiment, R¹ is selected from substituted or unsubstituted

and R³ is preferably substituted aryl. Even more preferred are those species in which Y is O.

In yet another embodiment, R⁷ and R⁸ are members independently selected from H, and substituted or unsubstituted alkyl.

Representative compounds according to Formula I are set forth in Example 12 and FIG. 1. Activities towards PN3 of selected compounds of the invention are provided in Table 1. The compound numbers in Table 1 are cross-referenced to Example 12.

TABLE 1 Activity in Compound # Flux Assay  34 +++ 150 +++ 160 +++ 181 +++ 185 ++ 188 +++ 189 +++ 198 +++ 200 +++ 203 ++ 206 +++ 208 +++ 221 ++ 300 +++ 304 ++ (+++ 0.1–4 μM; ++ 4.1–10 μM)

Also within the scope of the present invention are compounds of the invention that are poly- or multi-valent species, including, for example, species such as dimers, trimers, tetramers and higher homologs of the compounds of the invention or reactive analogues thereof. The poly- and multi-valent species can be assembled from a single species or more than one species of the invention. For example, a dimeric construct can be “homo-dimeric” or “heterodimeric.” Moreover, poly- and multi-valent constructs in which a compound of the invention or a reactive analogue thereof, is attached to an oligomeric or polymeric framework (e.g., polylysine, dextran, hydroxyethyl starch and the like) are within the scope of the present invention. The framework is preferably polyfunctional (i.e. having an array of reactive sites for attaching compounds of the invention). Moreover, the framework can be derivatized with a single species of the invention or more than one species of the invention.

Moreover, the present invention includes compounds within the motif set forth in Formulae I, which are functionalized to afford compounds having water-solubility that is enhanced relative to analogous compounds that are not similarly functionalized. Thus, any of the substituents set forth herein can be replaced with analogous radicals that have enhanced water solubility. For example, it is within the scope of the invention to, for example, replace a hydroxyl group with a diol, or an amine with a quaternary amine, hydroxy amine or similar more water-soluble moiety. In a preferred embodiment, additional water solubility is imparted by substitution at a site not essential for the activity towards the ion channel of the compounds set forth herein with a moiety that enhances the water solubility of the parent compounds. Methods of enhancing the water-solubility of organic compounds are known in the art. Such methods include, but are not limited to, functionalizing an organic nucleus with a permanently charged moiety, e.g., quaternary ammonium, or a group that is charged at a physiologically relevant pH, e.g. carboxylic acid, amine. Other methods include, appending to the organic nucleus hydroxyl- or amine-containing groups, e.g. alcohols, polyols, polyethers, and the like. Representative examples include, but are not limited to, polylysine, polyethyleneimine, poly(ethyleneglycol) and poly(propyleneglycol). Suitable functionalization chemistries and strategies for these compounds are known in the art. See, for example, Dunn, R. L., et al., Eds. POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS, ACS Symposium Series Vol. 469, American Chemical Society, Washington, D.C. 1991.

Preparation of Sodium Channel Inhibitors

Compounds of the present invention can be prepared using readily available starting materials or known intermediates. Examples of starting materials available from commercial suppliers include, but are not limited to 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one, 5-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one, 1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one, 1-piperidin-4-yl-1H-benzoimidazole hydrochloride, 2-methyl-1-piperidin-4-yl-1H-benzoimidazole hydrochloride, 7-Fluoro-1-piperidin-4-yl-1H-benzoimidazole hydrochloride and 2-phenyl-1-piperidin-4-yl-1H-benzoimidazole hydrochloride. Scheme 1 sets forth an exemplary synthetic scheme for the preparation of compounds of the invention.

In Scheme 1, the endocyclic nitrogen atom of the piperidine moiety of compound 1 is protected, forming a derivative bearing protecting group, P. The protected piperidine 2 is contacted with an alkylating agent R⁶—X, affording compound 3. The amine protecting group of compound 3 is removed to produce compound 4, which bears a piperidine moiety in which the endocyclic nitrogen atom is unprotected. Compound 4 is contacted with an alkylating, sulfonylating or acylating reagent (i.e.; R¹—X) yielding compound 5. Examples of appropriate acylating agents include, but are not limited to, R²CO₂H (e.g.; benzoic acid) and R²COCl (e.g.; benzoyl chloride and benzyl chloroformate). Examples of appropriate sulfonylating agents include, but are not limited to, R³SO₂Cl (e.g.; benzenesulfonyl chloride) and R³SO₂F (e.g.; benzenesulfonyl fluroride).

Additional compounds of the invention in which the carbonyl group of the cyclic urea is replaced with another group can be prepared using the synthetic pathway outlined in Scheme 2.

In Scheme 2, the 1-fluoro-2-nitro aromatic compound 6 is contacted with a piperidine amine 7 under conditions appropriate for fluoro displacement by the amine substituent of the piperidine, thereby forming compound 8. The nitro group of compound 8 is reduced to the corresponding amine group, affording compound 9. The 1,2-diaminobenzene substructure of compound 9 is converted to cyclic thiourea 10, which is S-alkylated, affording compound 11. One skilled in the art will recognize that compound 9 may be also converted to the cyclic urea (i.e.; compound 5, Scheme 1 where R⁶ is hydrogen). Compound 11 is oxidized to compound 12, which is converted into the corresponding amine by reaction with an amine HNR⁷R⁸, producing compound 13.

Still further compounds of the invention are available through the synthetic pathway set forth in Scheme 3.

Similar to Scheme 2, in Scheme 3, starting materials 6 and 7 are combined under conditions appropriate for fluoro group displacement affording compound 8. The nitro group is reduced to the amine 9 at which point Schemes 2 and 3 diverge. In Scheme 3, the amine of compound 9 is acylated with R⁹COCl to produce amide 14, which is subsequently cyclized to compound 15.

Scheme 4 sets forth an exemplary synthetic scheme for producing compounds of the invention in which the nitrogen of the cyclic urea system is not alkylated. In Scheme 4, starting piperidine 1 is treated with an alkylating, sulfonylating or acylating agent (i.e.; R¹—X) to produce compound 16. Examples of appropriate acylating agents include, but are not limited to, R²CO₂H (i.e.; benzoic acid) and R²COCl (i.e.; benzoyl chloride and benzyl chloroformate). Examples of appropriate sulfonylating agents include, but are not limited to, R³SO₂Cl (i.e; benzenesulfonyl chloride) and R³SO₂F (i.e.; benzenesulfonyl fluroride).

Scheme 5 sets forth an exemplary synthetic scheme for producing compounds of the invention in which the R¹ is

R⁴ is —NR¹⁵R¹⁶ and R⁵ is cyano. In Scheme 5 starting piperidine 1 is treated with diphenyl N-cyanocarbonimidate to produce compound 17. Compound 17 may be made to react with amine HNR¹⁵R¹⁶ to produce compound 18.

Scheme 6 sets forth an exemplary synthetic scheme for producing compounds of the invention in which R¹ is

and R¹ is —NR¹⁵R¹⁶. In Scheme 6, starting piperidine 1 is made to react with oxazolidinone intermediate 19 to produce compound 20. Methods used to produce intermediate 19 are known in the literature.

The alkylating, sulfonyating and acylating agents used in the reaction pathway set forth in Schemes 1-4 are of essentially any structure, e.g., substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted and unsubstituted heteroalkyl. Moreover, leaving groups, X, include, but are not limited to, halides, sulfonic esters, oxonium ions, alkyl perchlorates, ammonioalkanesulfonate esters, alkylfluorosulfonates and fluorinated compounds (e.g., triflates, nonaflates, tresylates) and the like. The choice of these and other leaving groups appropriate for a particular set of reaction conditions is within the abilities of those of skill in the art (see, for example, March J, ADVANCED ORGANIC CHEMISTRY, 2nd Edition, John Wiley and Sons, 1992; Sandler S R, Karo W, ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd Edition, Academic Press, Inc., 1983; and Wade L G, COMPENDIUM OF ORGANIC SYNTHETIC METHODS, John Wiley and Sons, 1980).

Methods for preparing dimers, trimers and higher homologs of small organic molecules, such as those of the present invention, as well as methods of functionalizing a polyfunctional framework molecule are well known to those of skill in the art. For example, an aromatic amine of the invention is converted to the corresponding isothiocyanate by the action of thiophosgene. The resulting isothiocyanate is coupled to an amine of the invention, thereby forming either a homo- or heterodimeric species. Alternatively, the isothiocyanate is coupled with an amine-containing backbone, such as polylysine, thereby forming a conjugate between a polyvalent framework and a compound of the invention. If it is desired to prepare a heterofuntionalized polyvalent species, the polylysine is underlabeled with the first isothiocyanate and subsequently labeled with one or more different isothiocyanates. Alternatively, a mixture of isothiocyanates is added to the backbone. Purification proceeds by, for example, size exclusion chromatography, dialysis, nanofiltration and the like.

II. Assays for Blockers of Sodium Ion Channels

PN3 monomers as well as PN3 alleles and polymorphic variants are subunits of sodium channels. The activity of a sodium channel comprising PN3 subunits can be assessed using a variety of in vitro and in vivo assays, e.g., measuring current, measuring membrane potential, measuring ion flux, e.g., sodium or guanidinium, measuring sodium concentration, measuring second messengers and transcription levels, and using e.g., voltage-sensitive dyes, radioactive tracers, and patch-clamp electrophysiology.

A number of experimental models in the rat are appropriate for assessing the efficacy of the compounds of the invention. For example, the tight ligation of spinal nerves described by Kim et al., Pain 50: 355-363 (1992) can be used to experimentally determine the effect of the compounds of the invention on a PN3 channel. For example, a sodium channel blockade in vitro assay can be used to determine the effectiveness of compounds of Formula I as sodium channel blockers in an in vitro model by the inhibition of compound action potential propagation in isolated nerve preparations (Kourtney and Stricharz, LOCAL ANESTHETICS, Springer-Verlag, New York, 1987). The mechanical allodynia in vivo assay is also of use in determining the efficacy of compounds of the invention (Kim and Chung Pain 50:355 (1992)). Mechanical sensitivity can be assessed using a procedure described by Chaplan et al., J. Neurosci. Methods 53: 55-63 (1994). Other assays of use are known to those of skill in the art. See, for example, Loughhead et al., U.S. Pat. No. 6,262,078.

Inhibitors of the PN3 sodium channels can be tested using biologically active recombinant PN3, or naturally occurring TTX-resistant sodium channels, or by using native cells, like cells from the nervous system expressing a PN3 channel. PN3 channels can be isolated, co-expressed or expressed in a cell, or expressed in a membrane derived from a cell. In such assays, PN3 is expressed alone to form a homomeric sodium channel or is co-expressed with a second subunit (e.g., another PN3 family member) so as to form a heteromeric sodium channel. Exemplary expression vectors include, but are not limited to, PN3-pCDNA3.1, and PN3-pOX. The PN3 channel is stably expressed in mammalian expression systems.

Inhibition can be tested using one of the in vitro or in vivo assays described above. Samples or assays that are treated with a potential sodium channel inhibitor or activator are compared to control samples without the test compound, to examine the extent of inhibition. Control samples (untreated with activators or inhibitors) are assigned a relative sodium channel activity value of 100. Inhibition of channels comprising PN3 is achieved when the sodium channel activity value relative to the control is less than 70%, preferably less than 40% and still more preferably, less than 30%. Compounds that decrease the flux of ions will cause a detectable decrease in the ion current density by decreasing the probability of a channel comprising PN3 being open, by decreasing conductance through the channel, decreasing the number of channels, or decreasing the expression of channels.

Changes in ion flux may be assessed by determining changes in polarization (i.e., electrical potential) of the cell or membrane expressing the sodium channel. A preferred means to determine changes in cellular polarization is by measuring changes in current or voltage with the voltage-clamp and patch-clamp techniques, using the “cell-attached” mode, the “inside-out” mode, the “outside-out” mode, the “perforated cell” mode, the “one or two electrode” mode, or the “whole cell” mode (see, e.g., Ackerman et al., New Engl. J. Med. 336: 1575-1595 (1997)). Whole cell currents are conveniently determined using the standard methodology (see, e.g., Hamil et al., Pflugers. Archiv. 391: 85 (1981). Other known assays include: radiolabeled rubidium flux assays and fluorescence assays using voltage-sensitive dyes (see, e.g., Vestergarrd-Bogind et al., J. Membrane Biol. 88: 67-75 (1988); Daniel et al., J. Pharmacol. Meth. 25: 185-193 (1991); Holevinsky et al., J. Membrane Biology 137: 59-70 (1994)). Assays for compounds capable of inhibiting or increasing sodium flux through the channel proteins can be performed by application of the compounds to a bath solution in contact with and comprising cells having a channel of the present invention (see, e.g., Blatz et al., Nature 323: 718-720 (1986); Park, J. Physiol. 481: 555-570 (1994)). Generally, the compounds to be tested are present in the range from about 1 pM to about 100 mM, preferably from about 1 pM to about 1 μM.

The effects of the test compounds upon the function of the channels can be measured by changes in the electrical currents or ionic flux or by the consequences of changes in currents and flux. Changes in electrical current or ionic flux are measured by either increases or decreases in flux of ions such as sodium or guanidinium ions (see, e.g., Berger et al., U.S. Pat. No. 5,688,830). The cations can be measured in a variety of standard ways. They can be measured directly by concentration changes of the ions or indirectly by membrane potential or by radio-labeling of the ions. Consequences of the test compound on ion flux can be quite varied. Accordingly, any suitable physiological change can be used to assess the influence of a test compound on the channels of this invention. The effects of a test compound can be measured by a toxin-binding assay. When the functional consequences are determined using intact cells or animals, one can also measure a variety of effects such as transmitter release, hormone release, transcriptional changes to both known and uncharacterized genetic markers, changes in cell metabolism such as cell growth or pH changes, and changes in intracellular second messengers such as Ca²⁺, or cyclic nucleotides.

High throughput screening (HTS) is of use in identifying promising candidates of the invention. Physiologically, Na channels open and close on a ms timescale. To overcome the short time in which channels are open the HTS assay can be run in the presence of an agent that modifies the gating of the channel, such as deltamethrin. This agent modifies the gating of Na channels and keeps the pore open for extended periods of time. In addition, while Na channels are primarily selective for Na, other monovalent cations can permeate the channel.

The specificity and effect of the PN3 blocking agents of the invention can also be assayed against non-specific blockers of PN3, such as tetracaine, mexilitine, and flecainide.

III. Pharmaceutical Compositions of Sodium Channel Openers

In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound of Formula I provided above.

Formulation of the Compounds (Compositions)

The compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and either a compound of Formula I, or a pharmaceutically acceptable salt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

IV. Methods for Inhibiting Ion Flow in Voltage-Dependent Sodium Channels

In yet another aspect, the present invention provides methods for decreasing ion flow through voltage dependent sodium channels in a cell, comprising contacting a cell containing the target ion channels with a sodium channel-inhibiting amount of a compound of Formula I provided above.

The methods provided in this aspect of the invention are useful for the diagnosis of conditions that can be treated by inhibiting ion flux through voltage-dependent sodium channels, or for determining if a patient will be responsive to therapeutic agents, which act by inhibiting sodium channels.

V. Methods for Treating Conditions Mediated by Voltage-Dependent Sodium Channels

In still another aspect, the present invention provides a method for the treatment of a disorder or condition through inhibtion of a voltage-dependent sodium channel. In this method, a subject in need of such treatment is administered an effective amount of a compound having the formula provided above. In a preferred embodiment, the compounds provided herein are used to treat a disorder or condition by inhibiting an ion channel of the voltage gated sodium channel family, e.g., PN3.

The compounds provided herein are useful as sodium channel inhibitors and find therapeutic utility via inhibition of voltage-dependent sodium channels in the treatment of diseases or conditions. The sodium channels that are typically inhibited are described herein as voltage-dependent sodium channels such as the PN3 sodium channels.

The compounds of the invention are particularly preferred for use in the treating, preventing or ameliorating pain or convulsions. The method includes administering to a patient in need of such treatment, a therapeutically effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof.

The compounds, compositions and methods of the present invention are of particular use in treating pain, including both inflammatory and neuropathic pain. Exemplary forms of pain treated by a compound of the invention include, postoperative pain, osteoarthritis pain, pain associated with metastatic cancer, neuropathy secondary to metastatic inflammation, trigeminal neuralgia, glossopharangyl neuralgia, adiposis dolorosa, burn pain, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, burn pain, pain following stroke, thalamic lesions, radiculopathy, and other forms of neuralgic, neuropathic, and idiopathic pain syndromes.

Idiopathic pain is pain of unknown origin, for example, phantom limb pain. Neuropathic pain is generally caused by injury or infection of the peripheral sensory nerves. It includes, but is not limited to pain from peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies.

Moreover, any sodium channel inhibitory substance possessed of satisfactory sodium channel inhibiting activity coupled with favorable intracranial transfer kinetics and metabolic stability is expected to show good efficacy in central nervous system (CNS) diseases and disorders such as central nervous system ischemia, central nervous system trauma (e.g. brain trauma, spinal cord injury, whiplash injury, etc.), epilepsy, neurodegenerative diseases (e.g. amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's chorea, Parkinson's disease, diabetic neuropathy, etc.), vascular dementia (e.g. multi-infarct dementia, Binswanger's disease, etc.), manic-depressive psychosis, depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine and cerebral edema.

In treatment of the above conditions, the compounds utilized in the method of the invention are administered at the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily. A daily dose range of about 0.1 mg/kg to about 100 mg/kg is more typical. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

EXAMPLES

The following examples are offered to illustrate, but not to limit the claimed invention.

In the examples below, unless otherwise stated, temperatures are given in degrees Celsius (° C.); operations were carried out at room or ambient temperature (typically a range of from about 18-25° C.; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (typically, 4.5-30 mmHg) with a bath temperature of up to 60° C.; the course of reactions was typically followed by TLC and reaction times are provided for illustration only; melting points are uncorrected; products exhibited satisfactory ¹H-NMR and/or microanalytical data; yields are provided for illustration only; and the following conventional abbreviations are also used: mp (melting point), L (liter(s)), mL (milliliters), mmol (millimoles), g (grams), mg (milligrams), min (minutes), LC-MS (liquid chromatography-mass spectrometry) and h (hours), PS (polystyrene), DIE (diisopropylethylamine).

Example 1

1.1 ¹⁴C Guanidinium Ion Influx Binding Assay

PN3 stably expressed in a host cell line were maintained in DMEM with 5% fetal bovine serum and 300 μg/ml G-418. The cells were subcultured and grown to confluence in 96-well plates 24-48 h before each experiment. After the growth medium was removed, the cells were washed with warm buffer (25 mM Hepes-Tris, 135 mM choline chloride, 5.4 mM potassium chloride, 0.98 mM magnesium sulfate, 5.5 mM glucose, and 1 mg/ml BSA, pH 7.4) and incubated in buffer on a 36° C. slide wanner for approximately 10 minutes. Various concentrations of the test compounds or standard sodium channel blockers (10 μM) and then deltamethrine (10 μM) were added to each well. After the cells were exposed to deltamethrine for 5 minutes, 5 μM of ¹⁴C-guanidinium was added, incubated with the radioligand (30-60 min), washed with ice-cold buffer, and dissolved in 0.1N sodium hydroxide. The radioactivity and the protein concentration of each cell lysate were determined by liquid scintillation counting and the protein assay using Pierce BCA reagent.

Example 2

2.1 Mechanical Allodynia In Vivo Assay

This assay determines the effectiveness of compounds of Formula I in relieving one of the symptoms in an in vivo model of neuropathic pain produced by spinal nerve ligation, namely mechanical allodynia.

Tactile allodynia was induced in rats using the procedures described by Kim and Chung, Pain 50: 355-363 (1992). Briefly, the rats were anesthetized with 2-5% inhaled isoflurane and maintained by 1% isoflurane. Each animal was then placed in a prone position, a 3 cm lateral incision was made, and the left paraspinal muscles separated from the spinous process at the L₄-S₂ level. The L₆ transverse process was then removed in order to visually identify the L₄-L₆ spinal nerves. The L₅ and L₆ spinal nerves were then individually isolated and tightly ligated with silk thread. The wound was then closed in layers by silk sutures. These procedures produced rats which developed a significant increase in sensitivity to mechanical stimuli that did not elicit a response in normal rats.

Mechanical sensitivity was assessed using a procedure described by Chaplan et al., J. Neurosci. Methods 53: 55-63 (1994). Briefly, a series of eight Von Frey filaments of varying rigidity strength were applied to the plantar surface of the hind paw ipsilaterial to the ligations with just enough force to bend the filament. The filaments were held in this position for no more than three seconds or until a positive allodynic response was displayed by the rat. A positive allodynic response consisted of lifting the affected paw followed immediately by licking or shaking of the paw. The order and frequency with which the individual filaments were applied were determined by using Dixon up-down method. Testing was initiated with the middle hair of the series with subsequent filaments being applied in consecutive fashion, either ascending or descending, depending on whether a negative or positive response, respectively, was obtained with the initial filament.

2.2 Thermal Hyperalgesia In Vivo Assay

This assay determines the effectiveness of compounds in relieving one of the symptoms of neuropathic pain produced by unilateral mononeuropathy, namely thermal hyperalgesia.

The rats having had surgery as described above were assessed for thermal hyperalgesia sensitivity at least 5-7 days post-surgery. Briefly, the rats were placed beneath inverted plexiglass cages upon an elevated glass platform and a radiant heat source beneath the glass was aimed at the plantar hindpaw. The duration of time before the hindpaw was withdrawn from the floor was measured to the nearest tenth of a second. The cutoff time for the heat stimulus was 40 seconds, and the light was calibrated such that this stimulus duration did not bum or blister the skin. Three latency measurements were taken for each hindpaw ipsilateral to the ligation in each test session, alternating left and right hindpaws, with greater than 1 minute intervals between tests.

2.3 Results

The results show that after oral administration the compounds of the invention produce efficacious anti-allodynic effects at doses less then or equal to 100 mg/kg. The results show that after IV administration the compounds of the invention produce efficacious anti-hyperalgesic effects at doses less than or equal to 30 mg/kg. Overall, the compounds of the present invention were found to be effective in reversing mechanical allodynia-like and thermal hyperalgesia-like symptoms.

Example 3

Preparation of 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

To a solution of 4-(2-keto-1-benzimidazolinyl)piperidine (0.34 g, 1.57 mmol) in methylene chloride (8 mL) was added pyridine (0.15 mL, 1.88 mmol) and 4-n-butylbenzoyl chloride (0.37 g, 1.88 mmol). The reaction mixture was stirred for 1 h then purified directly by column chromatography on silica gel by eluting with methylene chloride followed by ethyl acetate. The product fractions were combined and concentrated in vacuo. The residue was triturated with ethyl ether and the solids collected by filtration and rinsed with hexanes. 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (0.48 g; 81%) was obtained as white solid.

Example 4

Preparation of 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-5-fluoro-1,3-dihydro-benzoimidazol-2-one

4.1

A suspension of 1,4-difluoro-2-nitrobenzene (0.477 g, 3 mmol), ethyl 4-amino 1-piperidinecarboxylate (0.568 g, 3.3 mmol), and powdered potassium carbonate (0.456 g, 3.3 mmol) in dimethylformamide (5 mL) was stirred at 50° C. for 2 h. The reaction mixture was diluted with water then extracted with dichloromethane (5×30 mL). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel by eluting with methylene chloride followed by ethyl acetate. Product fractions were combined and evaporated in vacuo to give 4-(4-fluoro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester (0.761 g, 81%) as an orange solid.

4.2

4-(4-Fluoro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester (0.761 g, 2.45 mmol) (from step 1 above) was dissolved in methanol (10 mL) then hydrogenated over 10% Pd/C (balloon pressure). The hydrogenation was run until the orange color turned colorless. The reaction mixture was filtered through a celite pad, and the filtrate evaporated to a give 4-(2-amino-4-fluoro-phenylamino)-piperidine-1-carboxylic acid ethyl ester as a dark residue (0.679 g, 99%).

4.3

To a solution of 4-(2-amino-4-fluoro-phenylamino)-piperidine-1-carboxylic acid ethyl ester (0.100 g, 0.36 mmol) and triethylamine (0.110 mg, 1.08 mmol) in methylene chloride (2 mL) at 0° C. was added a solution of diphosgene (0.71 mg, 0.36 mmol) in methylene chloride (4 mL) at room temperature. The reaction mixture was stirred for 18 h then quenched with a saturated aqueous solution of sodium bicarbonate. The organic phase was separated and washed with brine. The organic phase was purified by passing it through a plug of silica gel, using ethyl acetate as the eluent. The filtrate was evaporated, in vacuo, to a residue. The residue was triturated with hexanes/dichlormethane (95:5) and the solid collected by filtration. Vaccum drying yielded 4-(5-fluoro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester (77.8 mg, 71%) as a light tan solid.

4.4

4-(5-Fluoro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester was refluxed with 10% sodium hydroxide (2 mL) for 4 h. The reaction was allowed to cool to room temperature and acidified with concentrated hydrochloric acid. The acidified reaction mixture was adjusted to pH 10 with the slow addition of sodium carbonate. The pink solid that formed was collected by filtration and vacuum dried to give 5-Fluoro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (29.4 mg, 73%).

4.5

To a solution of 5-fluoro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (29.4 mg, 0.125 mmol) in methylene chloride (1 mL) was added pyridine (0.12 μL, 0.15 mmol) and 4-n-butylbenzoyl chloride (26 μL, 0.138 mmol). The reaction mixture was stirred overnight then purified directly by column chromatography on silica gel by eluting with methylene chloride followed by ethyl acetate. The product fractions were combined and concentrated in vacuo to give 1-[1-(4-butyl-benzoyl)-piperidin-4-yl]-5-fluoro-1,3-dihydro-benzoimidazol-2-one (6.1 mg; 12%) was obtained as a glass.

Example 5

Preparation of 1-[1-(3-Trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Excess 3-Trifluoromethyl-benzenesulfonyl chloride and polystyrene-diisopropylethylamine resin (ca. 40 mg) were added to a 50 mM solution of 4-(2-keto-1-benzimidazolinyl)piperidine in methylene chloride-dimethyl formamide (9:1) (1 mL). The mixture was shaken 18 hours then scavenged with polystyrene-trisamine resin (ca. 33 mg) for another 18 hours. The reaction was filtered and evaporated to give 1-[1-(3-Trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (18.6 mg, 87%).

Example 6

Preparation of N-cyano-N′-ethyl-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxamidine

6.1

To a solution of 4-(2-keto-1-benzimidazolinyl)piperidine (1.3 g; 5.98 mmol) in acetonitrile was added diphenyl N-cyanocarbonimidate (1.56 g; 6.55 mmol; 1.1 equiv). The reaction mixture was stirred at 60° C. for 48 h under nitrogen atmosphere and then concentrated under reduced pressure. The crude product was suspended in ethyl acetate (50 mL) and a saturated aqueous solution of sodium bicarbonate (50 mL) and stirred overnight at room temperature. The solid was collected by filtration and dried to give N-cyano-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboximidic acid phenyl ester (1.85 g; 85%) as a white solid.

6.2

N-cyano-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboximidic acid phenyl ester (0.050 g; 0.14 mmol) was treated with a 2M Solution of ethylamine in tetrahydrofuran (2 mL) and subjected to microwave irradiation (temperature approximately 110° C.) for 0.5 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative reverse-phase liquid chromatography to give N-cyano-N′-ethyl-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxamidine (0.01 g) as a white solid.

Example 7

Preparation of (4-Butyl-phenyl)-[4-(2-thioxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-methanone

7.1

A suspension of 2-fluoronitrobenzene (1.41 g, 10 mmol), ethyl 4-amino 1-piperidinecarboxylate (2.00 g, 11.6 mmol), and powdered potassium carbonate (1.38 g, 10 mmol) in dimethylformamide (10 mL) was stirred for 18 h. The reaction mixture was diluted with water the extracted with ethyl ether (3×40 mL). The combined organic layers was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel by eluting with methylene chloride followed by ethyl acetate. Product fractions were combined and evaporated in vacuo to give 4-(2-nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester.

7.2

4-(2-Nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester (from step 1 above) was dissolved in methanol then hydrogenated over 10% Pd/C (balloon pressure). The hydrogenation was run until the yellow color turned colorless. It was filtered through a celite pad, and the filtrated evaporated to a reddish brown residue. The residue was triturated with 1% ethyl acetate in hexanes and the solid collected by filtration to give 4-(2-amino-phenylamino)-piperidine-1-carboxylic acid ethyl ester (2.02 g; 77%, 2 steps). ¹H NMR (CDCl₃) δ 1.27 (t, 3H, J=7.2), 1.4 (m, 2H), 2.05 (m, 2H), 3.0 (m, 2H), 3.4 (m, 4H), 4.1 (m, 4H), 6.7 (m, 4H)

7.3

To a solution of 4-(2-amino-phenylamino)-piperidine-1-carboxylic acid ethyl ester (0.76 g, 2.9 mmol) and triethylamine (0.81 ml, 5.8 mmol) in methylene chloride (10 mL) at 0° C. was added a solution of thiophosgene (0.22 mL, 2.9 mmol) in methylene chloride (10 mL) at room temperature. The reaction mixture was stirred for 2 h then quenched with 1N sodium hydroxide. The organic phase was separated and dried over sodium sulfate, filtered and concentrated. The crude product (i.e.; 4-(2-thioxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester) was treated with 10% sodium hydroxide (10 mL) and refluxed for 4 h. The reaction was allowed to cool to room temperature and the aqueous layer was washed with ethyl ether (50 mL), acidified to pH<2 with 6N hydrochloric acid, washed with ethyl ether (50 ml) and filtered (to remove a small amount of precipitated solid). The aqueous layer was adjusted to pH 10 by slowly adding sodium carbonate and then cooled to 0° C. The solid that formed was collected by filtration to give 1-piperidin-4-yl-1,3-dihydro-benzoimidazole-2-thione (0.2 g).

7.4

A solution of 1-piperidin-4-yl-1,3-dihydro-benzoimidazole-2-thione (0.2 g, 0.84 mmol) in methylene chloride (20 mL) was treated with pyridine (0.040 mL, 0.497 mmol) and 4-n-butylbenzoyl chloride (0.093 mL, 0.497 mmol). The reaction mixture was stirred for 18 h then purified directly by column chromatography on silica gel using ethyl acetate as the eluent to give (4-butyl-phenyl)-[4-(2-thioxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (0.167 g; 86%).

Example 8

Preparation of (4-butyl-phenyl)-[4-(2-hexylamino-benzoimidazol-1-yl)-piperidin-1-yl]-methanone

8.1

A solution of (4-butyl-phenyl)-[4-(2-thioxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (0.167 g, 0.424 mmol) in acetonitrile (5 mL) was treated with methyl iodide (0.120 g, 0.848 mmol) and potassium carbonate (0.117 g, 0.848 mmol). The reaction mixture was stirred 18 h then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate as the eluent to give (4-butyl-phenyl)-[4-(2-methylsulfanyl-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (0.164 g; 95%).

8.2

A solution of (4-butyl-phenyl)-[4-(2-methylsulfanyl-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (0.164 g, 0.403 mmol) in methylene chloride (15 mL) was treated with m-CPBA (0.180 g, 0.806 mmol) and stirred at room temperature for 1 h. LCMS analysis of the reaction mixture revealed that starting material still remained. Additional m-CPBA (0.090 g, 0.403 mmol) was added and the reaction mixture was allowed to stir 18 h at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate (3×20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give an oil. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as the eluent to give (4-butyl-phenyl)-[4-(2-methanesulfonyl-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (0.22 g).

8.3

In a sealed glass tube, (4-butyl-phenyl)-[4-(2-methanesulfonyl-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (9 mg) and hexyl amine (3 drops) were heated at 120-150° C. for 18 h. The crude product was taken into 1 ml 1:1 acetonitrile/water and purified via preparative liquid chromatography to give (4-butyl-phenyl)-[4-(2-hexylamino-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (4.8 mg).

Example 9

Preparation of 1-Allyl-3-[1-(4-butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (197.2 mg, 0.522 mmol), allyl bromide (260 μL, 3.0 mmol) and cesium carbonate (excess) were added to dimethyl formamide (3 mL) and the suspension was stirred at 120° C. in a sealed tube for 72 hours. The reaction was allowed to cool to room temperature and diluted with water (9 mL) then extracted with ethyl ether (2×10 mL). The combined organic phase was dried over sodium sulfate and purified by column chromatography on silica gel using ethyl ether as the eluent. The product fractions were combined and concentrated to give an oily residue. The residue was triturated with ethyl ether and the white crystals that formed were collected by filtration. Vacuum drying yielded 1-allyl-3-[1-(4-butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (144 mg, 66%) as a white crystalline solid.

Example 10

Preparation of (4-benzoimidazol-1-yl-piperidin-1-yl)-(4-butyl-phenyl)-methanone

p-Toluenesulfonic acid (catalytic amount) was added to a solution of [4-(2-amino-phenylamino)-piperidin-1-yl]-(4-butyl-phenyl)-methanone (50 mg, 0.142 mmol) and paraformaldehyde (500 mg) in acetonitrile (10 mL). The reaction was heated at 80° C. for 4 h. The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel using chloroform/methanol/ammonia (96:3.6:0.4) as the eluent. The product fractions were combined and evaporated to give (4-benzoimidazol-1-yl-piperidin-1-yl)-(4-butyl-phenyl)-methanone (39 mg, 76%) as an amber oil.

Example 11

Preparation of 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-sulfonic acid benzylamide

2-Oxo-oxazolidine-3-sulfonic acid benzylamide (0.059 g; 0.23 mmol; 1 equiv) was added to a solution of 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.050 mg; 0.23 mmol) in acetonitrile (2 mL). Triethylamine (32 μL; 0.23 mmol) was added and the reaction mixture was heated at 80° C. for 48 h. The reaction mixture was evaporated under reduced pressure and the crude product was purified by preparative liquid chromatography to provide 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-sulfonic acid benzylamide (0.010 g) as a white solid.

Example 12

Example 12 sets forth representative compounds of the invention.

compound # name MZ  1 1-{1-[3-(2-Chloro-phenyl)-5-methyl-isoxazole-4- 434 carbonyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-1,3- dihydro-benzoimidazol-2-one  2 1-[1-(5-Methyl-3-phenyl-isoxazole-4-carbonyl)- 400 1,2,3,6-tetrahydro-pyridin-4-yl]-1,3-dihydro- benzoimidazol-2-one  3 1-[1-(3,5-Dimethyl-isoxazole-4-carbonyl)-1,2,3,6- 338 tetrahydro-pyridin-4-yl]-1,3-dihydro-benzoimidazol- 2-one  4 1-{1-[3-(2,6-Dichloro-phenyl)-5-methyl-isoxazole- 468 4-carbonyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-1,3- dihydro-benzoimidazol-2-one  5 1-{1-[3-(2-Chloro-6-fluoro-phenyl)-5-methyl- 452 isoxazole-4-carbonyl]-1,2,3,6-tetrahydro-pyridin-4- yl}-1,3-dihydro-benzoimidazol-2-one  6 1-[1-(4-Chloro-1,3-dimethyl-1H-pyrazolo[3,4- 422 b]pyridine-5-carbonyl)-1,2,3,6-tetrahydro-pyridin-4- yl]-1,3-dihydro-benzoimidazol-2-one  7 1-[1-(5-Methyl-isoxazole-3-carbonyl)-1,2,3,6- 324 tetrahydro-pyridin-4-yl]-1,3-dihydro-benzoimidazol- 2-one  8 1-{1-[5-(4-Chloro-phenyl)-2-methyl-furan-3- carbonyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-1,3- 433 dihydro-benzoimidazol-2-one  9 1-[1-(4-Methoxy-benzenesulfonyl)-1,2,3,6- 385 tetrahydro-pyridin-4-yl]-1,3-dihydro-benzoimidazol- 2-one  10 1-[1-(2,5-Dimethoxy-benzenesulfonyl)-1,2,3,6- 415 tetrahydro-pyridin-4-yl]-1,3-dihydro-benzoimidazol- 2-one  11 1-[1-(3,4-Dichloro-benzenesulfonyl)-1,2,3,6- 423 tetrahydro-pyridin-4-yl]-1,3-dihydro-benzoimidazol- 2-one  12 1-[1-(4-Ethyl-benzenesulfonyl)-1,2,3,6-tetrahydro- 383 pyridin-4-yl]-1,3-dihydro-benzoimidazol-2-one  13 1-[1-(4-Trifluoromethoxy-benzenesulfonyl)-1,2,3,6- 439 tetrahydro-pyridin-4-yl]-1,3-dihydro-benzoimidazol- 2-one  14 1-[1-(2-Chloro-benzenesulfonyl)-1,2,3,6-tetrahydro- 389 pyridin-4-yl]-1,3-dihydro-benzoimidazol-2-one  15 1-[1-(5-Chloro-thiophene-2-sulfonyl)-1,2,3,6- 395 tetrahydro-pyridin-4-yl]-1,3-dihydro-benzoimidazol- 2-one  16 1-[1-(3,4-Dimethoxy-benzenesulfonyl)-1,2,3,6- 415 tetrahydro-pyridin-4-yl]-1,3-dihydro-benzoimidazol- 2-one  17 1-[1-(2,4-Dichloro-benzoyl)-1,2,3,6-tetrahydro- 387 pyridin-4-yl]-1,3-dihydro-benzoimidazol-2-one  18 1-[1-(3-Methoxy-benzoyl)-1,2,3,6-tetrahydro- 349 pyridin-4-yl]-1,3-dihydro-benzoimidazol-2-one  19 1-[1-(4-Trifluoromethyl-benzoyl)-1,2,3,6-tetrahydro- 387 pyridin-4-yl]-1,3-dihydro-benzoimidazol-2-one  20 1-[1-(2,2-Dimethyl-propionyl)-1,2,3,6-tetrahydro- 299 pyridin-4-yl]-1,3-dihydro-benzoimidazol-2-one  21 1-(1-Isobutyryl-1,2,3,6-tetrahydro-pyridin-4-yl)-1,3- 285 dihydro-benzoimidazol-2-one  22 1-(1-Phenylacetyl-1,2,3,6-tetrahydro-pyridin-4-yl)- 333 1,3-dihydro-benzoimidazol-2-one  23 1-[1-(3-Phenyl-acryloyl)-1,2,3,6-tetrahydro-pyridin- 345 4-yl]-1,3-dihydro-benzoimidazol-2-one  24 1-[1-(3-Methyl-butyryl)-1,2,3,6-tetrahydro-pyridin- 299 4-yl]-1,3,dihydro-benzoimidazol-2-one  25 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one 217  26 1-Nonanoyl-3-(1-nonanoyl-piperidin-4-yl)-1,3- 497 dihydro-benzoimidazol-2-one  27 1-(1-Nonanoyl-piperidin-4-yl)-1,3-dihydro- 357 benzoimidazol-2-one  28 1-[1-(Naphthalene-2-carbonyl)-piperidin-4-yl]-1,3- 371 dihydro-benzoimidazol-2-one  29 1-[1-(3-Trifluoromethyl-benzoyl)-piperidin-4-yl]- 389 1,3-dihydro-benzoimidazol-2-one  30 1-[1-(3,4-Difluoro-benzoyl)-piperidin-4-yl]-1,3- 357 dihydro-benzoimidazol-2-one  31 1-[1-(4-Ethyl-benzoyl)-piperidin-4-yl]-1,3-dihydro- 349 benzoimidazol-2-one  32 1-[1-(2-Fluoro-3-trifluoromethyl-benzoyl)-piperidin- 407 4-yl]-1,3-dihydro-benzoimidazol-2-one  33 1-[1-(4-Fluoro-3-trifluoromethyl-benzoyl)-piperidin- 407 4-yl]-1,3-dihydro-benzoimidazol-2-one  34 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro- 377 benzoimidazol-2-one  35 1-[1-(Pyridine-3-carbonyl)-piperidin-4-yl]-1,3- 322 dihydro-benzoimidazol-2-one  36 1-[1-(Benzo[1,3]dioxole-5-carbonyl)-piperidin-4-yl]- 365 1,3-dihydro-benzoimidazol-2-one  37 1-[1-(3-Fluoro-benzoyl)-piperidin-4-yl]-1,3-dihydro- 339 benzoimidazol-2-one  38 1-[1-(2-Cyclopentyl-acetyl)-piperidin-4-yl]-1,3- 327 dihydro-benzoimidazol-2-one  39 1-(1-Diphenylacetyl-piperidin-4-yl)-1,3-dihydro- 411 benzoimidazol-2-one  40 1-[1-(Furan-2-carbonyl)-piperidin-4-yl]-1,3-dihydro- 311 benzoimidazol-2-one  41 1-[1-(3-Phenyl-propionyl)-piperidin-4-yl]-1,3- 349 dihydro-benzoimidazol-2-one  42 1-[1-(6-Chloro-pyridine-3-carbonyl)-piperidin-4-yl]- 356 1,3-dihydro-benzoimidazol-2-one  43 1-[1-(2-Phenoxy-acetyl)-piperidin-4-yl]-1,3-dihydro- 351 benzoimidazol-2-one  44 1-{1-[2-(3,4-Dimethoxy-phenyl)-acetyl]-piperidin- 395 4-yl}-1,3-dihydro-benzoimidazol-2-one  45 1-[1-(Thiophene-2-carbonyl)-piperidin-4-yl]-1,3- 327 dihydro-benzoimidazol-2-one  46 1-[1-(3-Methyl-butyryl)-piperidin-4-yl]-1,3-dihydro- 301 benzoimidazol-2-one  47 1-[1-(3-Phenyl-acryloyl)-piperidin-4-yl]-1,3-dihydro 347 benzoimidazol-2-one  48 1-[1-(Quinoxaline-2-carbonyl)-piperidin-4-yl]-1,3- 373 dihydro-benzoimidazol-2-one  49 4-Oxo-4-[4-(2-oxo-2,3-dihydro-benzoimidazol-l-yl)- 331 piperidin-1-yl]-butyric acid methyl ester  50 1-{1-[1-(4-Chloro-phenyl)-cyclopentanecarbonyl]- 423 piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one  51 1-[1-(2-Phenyl-cyclopropanecarbonyl)-piperidin-4- 361 yl]-1,3-dihydro-benzoimidazol-2-one  52 1-[1-(5-Methyl-2-phenyl-2H-[1,2,3]triazole-4- 402 carbonyl)-piperidin-4-yl]-1,3-dihydro- benzoimidazol-2-one  53 1-[1-(5-Bromo-pyridine-3-carbonyl)-piperidin-4-yl]- 400 1,3-dihydro-benzoimidazol-2-one  54 1-(1-Cyclopentanecarbonyl-piperidin-4-yl)-1,3- 313 dihydro-benzoimidazol-2-one  55 1-[1-(2-p-Tolyloxy-pyridine-3-carbonyl)-piperidin- 428 4-yl]-1,3-dihydro-benzoimidazol-2-one  56 1-[1-(5-Nitro-furan-2-carbonyl)-piperidin-4-yl]-1,3- 356 dihydro-benzoimidazol-2-one  57 1-[1-(3,5-Dimethyl-isoxazole-4-carbonyl)-piperidin- 340 4-yl]-1,3-dihydro-benzoimidazol-2-one  58 1-[1-(4-Butyl-benzenesulfonyl)-piperidin-4-yl]-1,3- 413 dihydro-benzoimidazol-2-one  59 1-(1-Acetyl-piperidin-4-yl)-1,3-dihydro- 259 benzoimidazol-2-one  60 1-[1-(4-Methyl-benzoyl)-piperidin-4-yl]-1,3- 335 dihydro-benzoimidazol-2-one  61 1-(1-Phenylacetyl-piperidin-4-yl)-1,3-dihydro- 335 benzoimidazol-2-one  62 1-[1-(Biphenyl-4-carbonyl)-piperidin-4-yl]-1,3- 397 dihydro-benzoimidazol-2-one  63 3-[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)- 346 piperidine-1-carbonyl]-benzonitrile  64 1-[1-(4-Methoxy-benzoyl)-piperidin-4-yl]-1,3- 351 dihydro-benzoimidazol-2-one  65 1-[1-(3-Trifluoromethyl-benzenesulfonyl)-piperidin- 425 4-yl]-1,3-dihydro-benzoimidazol-2-one  66 1-(1-Methanesulfonyl-piperidin-4-yl)-1,3-dihydro- 295 benzoimidazol-2-one  67 1-[1-(4-Isopropyl-benzenesulfonyl)-piperidin-4-yl]- 399 1,3-dihydro-benzoimidazol-2-one  68 1-[1-(4-Chloro-benzenesulfonyl)-piperidin-4-yl]-1,3- 391 dihydro-benzoimidazol-2-one  69 1-[1-(Toluene-4-sulfonyl)-piperidin-4-yl]-1,3- 371 dihydro-benzoimidazol-2-one  70 1-[1-(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4- 417 yl]-1,3-dihydro-benzoimidazol-2-one  71 1-[1-(Naphthalene-1-sulfonyl)-piperidin-4-yl]-1,3- 407 dihydro-benzoimidazol-2-one  72 1-[1-(2-Nitro-benzenesulfonyl)-piperidin-4-yl]-1,3- 402 dihydro-benzoimidazol-2-one  73 1-[1-(1-Methyl-3H-imidazole-4-sulfonyl)-piperidin- 4-yl]-1,3-dihydro-benzoimidazol-2-one  74 1-[1-(2-Bromo-benzenesulfonyl)-piperidin-4-yl]-1,3- 435 dihydro-benzoimidazol-2-one  75 1-[1-(2-Nitro-phenylmethanesulfonyl)-piperidin- 416 4-yl]-1,3-dihydro-benzoimidazol-2-one  76 1-[1-(2-Methyl-5-nitro-benzenesulfonyl)-piperidin- 416 4-yl]-1,3-dihydro-benzoimidazol-2-one  77 1-[1-(4-Nitro-benzenesulfonyl)-piperidin-4-yl]-1,3- 402 dihydro-benzoimidazol-2-one  78 1-[1-(2,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]- 425 1,3-dihydro-benzoimidazol-2-one  79 1-[1-(3,4-Dimethoxy-benzenesulfonyl)-piperidin-4- 417 yl]-1,3-dihydro-benzoimidazol-2-one  80 1-[1-(4-Bromo-benzenesulfonyl)-piperidin-4-yl]-1,3- 435 dihydro-benzoimidazol-2-one  81 1-[1-(5-Chloro-4-nitro-thiophene-2-sulfonyl)- 442 piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one  82 1-[1-(3-Nitro-benzenesulfonyl)-piperidin-4-yl]-1,3- 402 dihydro-benzoimidazol-2-one  83 1-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]- 413 1,3-dihydro-benzoimidazol-2-one  84 1-[1-(2,4-Dinitro-benzenesulfonyl)-piperidin-4-yl]- 447 1,3-dihydro-benzoimidazol-2-one  85 1-[1-(4-Chloro-3-nitro-benzenesulfonyl)-piperidin- 436 4-yl]-1,3-dihydro-benzoimidazol-2-one  86 1-[1-(3,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]- 425 1,3-dihydro-benzoimidazol-2-one  87 1-[1-(7,7-Dimethyl-2-oxo-bicyclo[2.2.1]hept-1- 431 ylmethanesulfonyl)-piperidin-4-yl]-1,3-dihydro- benzoimidazol-2-one  88 1-[1-(4-Acetyl-benzenesulfonyl)-piperidin-4-yl]-1,3- 399 dihydro-benzoimidazol-2-one  89 1-[1-(2,3-Dichloro-benzenesulfonyl)-piperidin-4-yl]- 425 1,3-dihydro-benzoimidazol-2-one  90 1-[1-(5-Bromo-2-methoxy-benzenesulfonyl)- 465 piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one  91 1-[1-(4-Pentyl-benzenesulfonyl)-piperidin-4-yl]-1,3- 427 dihydro-benzoimidazol-2-one  92 2-[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)- 382 piperidine-1-sulfonyl]-benzonitrile  93 1-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin- 376 4-yl]-1,3-dihydro-benzoimidazol-2-one  94 1-[1-(2-Nitro-4-trifluoromethyl-benzenesulfonyl)- 470 piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one  95 1-[1-(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-1,3- 375 dihydro-benzoimidazol-2-one  96 1-[1-(3,5-Bis-trifluoromethyl-benzenesulfonyl)- 493 piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one  97 1-(1-Benzenesulfonyl-piperidin-4-yl)-1,3-dihydro- 357 benzoimidazol-2-one  98 1-[1-(3,4-Difluoro-benzenesulfonyl)-piperidin-4- 393 yl]-1,3-dihydro-benzoimidazol-2-one  99 1-[1-(Butane-1-sulfonyl)-piperidin-4-yl]-1,3- 337 dihydro-benzoimidazol-2-one 100 1-[1-(2,4-Difluoro-benzenesulfonyl)-piperidin-4- 393 yl]-1,3-dihydro-benzoimidazol-2-one 101 1-(1-Ethanesulfonyl-piperidin-4-yl)-1,3-dihydro- 309 benzoimidazol-2-one 102 1-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-4- 425 yl]-1,3-dihydro-benzoimidazol-2-one 103 1-[1-(4-Trifluoromethoxy-benzenesulfonyl)- 441 piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one 104 1-[1-(4-Ethyl-benzenesulfonyl)-piperidin-4-yl]-1,3- 385 dihydro-benzoimidazol-2-one 105 1-[1-(Nonafluorobutane-1-sulfonyl)-piperidin-4- 499 yl]-1,3-dihydro-benzoimidazol-2-one 106 1-[1-(3-Chloro-benzenesulfonyl)-piperidin-4-yl]-1,3- 391 dihydro-benzoimidazol-2-one 107 1-[1-(4-Propyl-benzenesulfonyl)-piperidin-4-yl]-1,3- 399 dihydro-benzoimidazol-2-one 108 1-[1-(2-Fluoro-benzenesulfonyl)-piperidin-4-yl]-1,3- 375 dihydro-benzoimidazol-2-one 109 1-[1-(Toluene-3-sulfonyl)-piperidin-4-yl]-1,3- 371 dihydro-benzoimidazol-2-one 110 1-[1-(4-tert-Butyl-benzoyl)-piperidin-4-yl]-1,3- 377 dihydro-benzoimidazol-2-one 111 1-(1-Cyclohexanecarbonyl-piperidin-4-yl)-1,3- 327 dihydro-benzoimidazol-2-one 112 1-[1-(3-Chloro-benzoyl)-piperidin-4-yl]-1,3-dihydro- 355 benzoimidazol-2-one 113 1-(1-Butyryl-piperidin-4-yl)-1,3-dihydro- 287 benzoimidazol-2-one 114 1-(1-Propionyl-piperidin-4-yl)-1,3-dihydro- 273 benzoimidazol-2-one 115 1-[1-(3-Cyclopentyl-propionyl)-piperidin-4-yl]-1,3- 341 dihydro-benzoimidazol-2-one 116 1-(1-Pentanoyl-piperidin-4-yl)-1,3-dihydro- 301 benzoimidazol-2-one 117 1-[1-(2,2-Dimethyl-propionyl)-piperidin-4-yl]-1,3- 301 dihydro-benzoimidazol-2-one 118 1-[1-(3,5-Bis-trifluoromethyl-benzoyl)-piperidin-4- 457 yl]-1,3-dihydro-benzoimidazol-2-one 119 1-[1-(2-Methoxy-acetyl)-piperidin-4-yl]-1,3- 289 dihydro-benzoimidazol-2-one 120 1-{1-[2-(4-Chloro-phenyl)-acetyl]-piperidin-4-yl}- 369 1,3-dihydro-benzoimidazol-2-one 121 1-[1-(Morpholine-4-carbonyl)-piperidin-4-yl]-1,3- 330 dihydro-benzoimidazol-2-one 122 1-[1-(4-Chloro-benzoyl)-piperidin-4-yl]-1,3-dihydro- 355 benzoimidazol-2-one 123 1-[1-(2,4-Difluoro-benzoyl)-piperidin-4-yl]-1,3- 357 dihydro-benzoimidazol-2-one 124 1-[1-(2,6-Difluoro-benzoyl)-piperidin-4-yl]-1,3- 357 dihydro-benzoimidazol-2-one 125 1-[1-(1-Phenyl-5-propyl-1H-pyrazole-4-carbonyl)- 429 piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one 126 1-(1-Cyclobutanecarbonyl-piperidin-4-yl)-1,3- 299 dihydro-benzoimidazol-2-one 127 1-[1-(5-tert-Butyl-2-methyl-2H-pyrazole-3- 381 carbonyl)-piperidin-4-yl]-1,3-dihydro- benzoimidazol-2-one 128 1-[1-(3,5-Difluoro-benzoyl)-piperidin-4-yl]-1,3- 357 dihydro-benzoimidazol-2-one 129 1-[1-(2-Thiophen-2-yl-acetyl)-piperidin-4-yl]-1,3- 341 dihydro-benzoimidazol-2-one 130 1-{1-[2-(4-Methoxy-phenyl)-acetyl]-piperidin-4- 365 yl}-1,3-dihydro-benzoimidazol-2-one 131 1-[1-(4-Propyl-benzoyl)-piperidin-4-yl]-1,3-dihydro- 363 benzoimidazol-2-one 132 1-[1-(3-Methyl-benzoyl)-piperidin-4-yl]-1,3- 335 dihydro-benzoimidazol-2-one 133 1-[1-(2,3-Difluoro-benzoyl)-piperidin-4-yl]-1,3- 357 dihydro-benzoimidazol-2-one 134 1-[1-(Isoxazole-5-carbonyl)-piperidin-4-yl]-1,3- 312 dihydro-benzoimidazol-2-one 135 1-[1-(2,4,5-Trifluoro-benzoyl)-piperidin-4-yl]-1,3- 375 dihydro-benzoimidazol-2-one 136 1-[1-(2,5-Difluoro-benzoyl)-piperidin-4-yl]-1,3- 357 dihydro-benzoimidazol-2-one 137 1-{1-[2-(4-Fluoro-phenyl)-acetyl]-piperidin-4-yl}- 353 1,3-dihydro-benzoimidazol-2-one 138 1-{1-[2-(3-Methoxy-phenyl)-acetyl]-piperidin-4-yl}- 365 1,3-dihydro-benzoimidazol-2-one 139 1-[1-(4-Ethoxy-benzoyl)-piperidin-4-yl]-1,3- 365 dihydro-benzoimidazol-2-one 140 1-[1-(2-Chloro-benzoyl)-piperidin-4-yl]-1,3-dihydro- 355 benzoimidazol-2-one 141 1-[1-(2-Methoxy-benzoyl)-piperidin-4-yl]-1,3- 351 dihydro-benzoimidazol-2-one 142 1-[1-(2-Fluoro-4-trifluoromethyl-benzoyl)- 407 piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one 143 1-[1-(2,3,4-Trifluoro-benzoyl)-piperidin-4-yl]-1,3- 375 dihydro-benzoimidazol-2-one 144 1-[1-(2,3-Difluoro-4-methyl-benzoyl)-piperidin-4- 371 yl]-1,3-dihydro-benzoimidazol-2-one 145 1-[1-(3-Chloro-2,4-difluoro-benzoyl)-piperidin-4- 391 yl]-1,3-dihydro-benzoimidazol-2-one 146 1-[1-(5-Methyl-isoxazole-3-carbonyl)-piperidin-4- 326 yl]-1,3-dihydro-benzoimidazol-2-one 147 1-{1-[5-(4-Chloro-phenyl)-2-methyl-furan-3- 435 carbonyl]-piperidin-4-yl}-1,3-dihydro- benzoimidazol-2-one 148 1-[1-(Adamantane-1-carbonyl)-piperidin-4-yl]-1,3- 379 dihydro-benzoimidazol-2-one 149 1-[1-(3,4-Dichloro-benzoyl)-piperidin-4-yl]-1,3- 389 dihydro-benzoimidazol-2-one 150 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-methyl-1,3- 391 dihydro-benzoimidazol-2-one 151 4-(2-Oxo-5-trifluoromethyl-2,3-dihydro- 357 benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester 152 1-[1-(4-Pentyl-benzoyl)-piperidin-4-yl]-1,3-dihydro- 391 benzoimidazol-2-one 153 1-[1-(4-Hexyl-benzoyl)-piperidin-4-yl]-1,3-dihydro- 405 benzoimidazol-2-one 154 1-[1-(4-Heptyl-benzoyl)-piperidin-4-yl]-1,3-dihydro- 419 benzoimidazol-2-one 155 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-5- 445 trifluoromethyl-1,3-dihydro-benzoimidazol-2-one 156 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3- 405 ethyl-1,3-dihydro-benzoimidazol-2-one 157 1-Benzyl-3-[1-(4-butyl-benzoyl)-piperidin-4-yl]-1,3- 467 dihydro-benzoimidazol-2-one 158 1-[1-(4-Cyclohexyl-benzoyl)-piperidin-4-yl]-1,3- 403 dihydro-benzoimidazol-2-one 159 4-(5-Fluoro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)- 307 piperidine-1-carboxylic acid ethyl ester 160 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-5-fluoro-1,3- 395 dihydro-benzoimidazol-2-one 161 1-[1-(4-Ethoxymethyl-benzoyl)-piperidin-4-yl]-1,3- 379 dihydro-benzoimidazol-2-one 162 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-propyl-1,3- 419 dihydro-benzoimidazol-2-one 163 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3- 431 cyclopropylmethyl-1,3-dihydro-benzoimidazol- 2-one 164 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(3-methyl- 447 butyl)-1,3-dihydro-benzoimidazol-2-one 165 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-isobutyl- 433 1,3-dihydro-benzoimidazol-2-one 166 1-Allyl-3-[1-(4-butyl-benzoyl)-piperidin-4-yl]-1,3- 417 dihydro-benzoimidazol-2-one 167 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-pyridin-2- 468 ylmethyl-1,3-dihydro-benzoimidazol-2-one 168 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-pyridin-3- 468 ylmethyl-1,3-dihydro-benzoimidazol-2-one 169 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(4-methyl- 481 benzyl)-1,3-dihydro-benzoimidazol-2-one 170 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(4-tert- 523 butyl-benzyl)-1,3-dihydro-benzoimidazol-2-one 171 1-(4-Bromo-benzyl)-3-[1-(4-butyl-benzoyl)- 545 piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one 172 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(4-chloro- 501 benzyl)-1,3-dihydro-benzoimidazol-2-one 173 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(4- 535 trifluoromethyl-benzyl)-1,3-dihydro-benzoimidazol- 2-one 174 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(4- 551 trifluoromethoxy-benzyl)-1,3-dihydro- benzoimidazol-2-one 175 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(4- 545 methanesulfonyl-benzyl)-1,3-dihydro- benzoimidazol-2-one 176 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(2-chloro- 501 benzyl)-1,3-dihydro-benzoimidazol-2-one 177 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(3-chloro- 501 benzyl)-1,3-dihydro-benzoimidazol-2-one 178 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(3- 497 methoxy-benzyl)-1,3-dihydro-benzoimidazol-2-one 179 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(2- 535 trifluoromethyl-benzyl)-1,3-dihydro-benzoimidazol- 2-one 180 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(3- 535 trifluoromethyl-benzyl)-1,3-dihydro-benzoimidazol- 2-one 181 1-[1-(4-Butyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 375 4-yl]-1,3-dihydro-benzoimidazol-2-one 182 1-[1-(4-Pentyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 389 4-yl]-1,3-dihydro-benzoimidazol-2-one 183 1-[1-(4-Hexyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 403 4-yl]-1,3-dihydro-benzoimidazol-2-one 184 1-[1-(4-Heptyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 417 4-yl]-1,3-dihydro-benzoimidazol-2-one 185 (4-Butyl-phenyl)-(4-{2-[(pyridin-2-ylmethyl)- 467 amino]-benzoimidazol-1-yl}-piperidin-1-yl)- methanone 186 (4-Butyl-phenyl)-{4-[2-(3-cyclohexylamino- 515 propylamino)-benzoimidazol-1-yl]-piperidin-1-yl}- methanone 187 (4-Butyl-phenyl)-{4-[2-(3-diethylamino- 489 propylamino)-benzoimidazol-1-yl]-piperidin-1-yl}- methanone 188 (4-Butyl-phenyl)-[4-(2-hexylamino-benzoimidazol- 460 1-yl)-piperidin-1-yl]-methanone 189 1-[1-(4-Butyl-benzyl)-piperidin-4-yl]-1,3-dihydro- 363 benzoimidazol-2-one 190 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(2- 448 dimethylamino-ethyl)-1,3-dihydro-benzoimidazol- 2-one 191 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(2- 490 morpholin-4-yl-ethyl)-1,3-dihydro-benzoimidazol- 2-one 192 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(2-methyl- 488 thiazol-4-ylmethyl)-1,3-dihydro-benzoimidazol- 2-one 193 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-[2-(1- 488 methyl-pyrrolidin-2-yl)-ethyl]-1,3-dihydro- benzoimidazol-2-one 194 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(2- 488 piperidin-1-yl-ethyl)-1,3-dihydro-benzoimidazol- 2-one 195 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(3,5- 486 dimethyl-isoxazol-4-ylmethyl)-1,3-dihydro- benzoimidazol-2-one 196 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(tetrahydro- 475 pyran-2-ylmethyl)-1,3-dihydro-benzoimidazol-2-one 197 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-(tetrahydro- 461 furan-2-ylmethyl)-1,3-dihydro-benzoimidazol-2-one 198 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-3-pyridin-4- 468 ylmethyl-1,3-dihydro-benzoimidazol-2-one 199 1-(1-Benzoyl-piperidin-4-yl)-1,3-dihydro- 321 benzoimidazol-2-one 200 3-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro- 378 imidazo[4,5-b]pyridin-2-one 201 3-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-7-methyl- 392 1,3-dihydro-imidazo[4,5-b]pyridin-2-one 202 1-{1-[4-(1-Methyl-butyl)-benzoyl]-piperidin-4-yl}- 391 1,3-dihydro-benzoimidazol-2-one 203 (4-Butyl-phenyl)-[4-(2-methyl-benzoimidazol-1-yl)- 375 piperidin-1-yl]-methanone 204 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)- 392 piperidine-1-carboxylic acid (4-butyl-phenyl)-amide 205 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-5,6-dichloro- 445 1,3-dihydro-benzoimidazol-2-one 206 1-[1-(4-Butyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 389 4-yl]-3-methyl-1,3-dihydro-benzoimidazol-2-one 207 1-[1-(4-Butyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 403 4-yl]-3-ethyl-1,3-dihydro-benzoimidazol-2-one 208 1-Benzyl-3-[1-(4-butyl-benzoyl)-1,2,3,6-tetrahydro- 465 pyridin-4-yl]-1,3-dihydro-benzoimidazol-2-one 209 1-[1-(4-Butyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 499 4-yl]-3-(3-chloro-benzyl)-1,3-dihydro- benzoimidazol-2-one 210 1-Allyl-3-[1-(4-butyl-benzoyl)-1,2,3,6-tetrahydro- 415 pyridin-4-yl]-1,3-dihydro-benzoimidazol-2-one 211 1-[1-(4-Butyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 499 4-yl]-3-(4-chloro-benzyl)-1,3-dihydro- benzoimidazol-2-one 212 1-[1-(4-Butyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 459 4-yl]-3-(tetrahydro-furan-2-ylmethyl)-1,3-dihydro- benzoimidazol-2-one 213 1-[1-(4-Butyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 484 4-yl]-3-(3,5-dimethyl-isoxazol-4-ylmethyl)-1,3- dihydro-benzoimidazol-2-one 214 1-[1-(4-Butyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 466 4-yl]-3-pyridin-4-ylmethyl-1,3-dihydro- benzoimidazol-2-one 215 1-[1-(4-Butyl-benzoyl)-1,2,3,6-tetrahydro-pyridin- 466 4-yl]-3-pyridin-3-ylmethyl-1,3-dihydro- benzoimidazol-2-one 216 (4-Butyl-phenyl)-{4-[2-(2-hydroxy-ethylamino)- 420 benzoimidazol-1-yl]-piperidin-1-yl}-methanone 217 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)- 317 piperidine-1-carboxylic acid tert-butyl ester 218 4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1- 331 yl)-piperidine-1-carboxylic acid tert-butyl ester 219 (4-Butyl-phenyl)-[4-2-trifluoromethyl- 429 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 220 1-Methyl-3-piperidin-4-yl-1,3-dihydro- 231 benzoimidazol-2-one 221 1-(1-Benzyl-piperidin-4-yl)-3-methyl-1,3-dihydro- 321 benzoimidazol-2-one 222 1-[1-(4-Chloro-benzyl)-piperidin-4-yl]-3-methyl-1,3- 355 dihydro-benzoimidazol-2-one 223 1-[1-(4-tert-Butyl-benzyl)-piperidin-4-yl]-3- 377 methyl-1,3-dihydro-benzoimidazol-2-one 224 1-[1-(2-Methoxy-benzyl)-piperidin-4-yl]-3-methyl- 351 1,3-dihydro-benzoimidazol-2-one 225 1-[1-(3,5-Difluoro-benzyl)-piperidin-4-yl]-3- 357 methyl-1,3-dihydro-benzoimidazol-2-one 226 1-Methyl-3-[1-(3-methyl-benzyl)-piperidin-4-yl]- 335 1,3-dihydro-benzoimidazol-2-one 227 1-[1-(2-Chloro-benzyl)-piperidin-4-yl]-3-methyl-1,3- 355 dihydro-benzoimidazol-2-one 228 1-[1-(3-Chloro-benzyl)-piperidin-4-yl]-3-methyl-1,3- 355 dihydro-benzoimidazol-2-one 229 1-[1-(2,4-Dichloro-benzyl)-piperidin-4-yl]-3- 389 methyl-1,3-dihydro-benzoimidazol-2-one 230 1-[1-(3,5-Dimethyl-isoxazol-4-ylmethyl)-piperidin- 340 4-yl]-3-methyl-1,3-dihydro-benzoimidazol-2-one 231 1-[1-(3,4-Dichloro-benzyl)-piperidin-4-yl]-3- 389 methyl-1,3-dihydro-benzoimidazol-2-one 232 1-[1-(4-Methoxy-benzyl)-piperidin-4-yl]-3-methyl- 351 1,3-dihydro-benzoimidazol-2-one 233 1-[1-(3-Fluoro-5-trifluoromethyl-benzyl)-piperidin- 407 4-yl]-3-methyl-1,3-dihydro-benzoimidazol-2-one 234 1-Methyl-3-[1-(3-trifluoromethyl-benzyl)-piperidin- 389 4-yl]-1,3-dihydro-benzoimidazol-2-one 235 1-Methyl-3-[1-(2-methyl-benzyl)-piperidin-4-yl]- 335 1,3-dihydro-benzoimidazol-2-one 236 1-Methyl-3-(1-pyridin-2-ylmethyl-piperidin-4-yl)- 322 1,3-dihydro-benzoimidazol-2-one 237 1-Methyl-3-[1-(4-methyl-benzyl)-piperidin-4-yl]- 335 1,3-dihydro-benzoimidazol-2-one 238 1-Methyl-3-[1-(2-trifluoromethyl-benzyl)-piperidin- 389 4-yl]-1,3-dihydro-benzoimidazol-2-one 239 1-[1-(4-Bromo-benzyl)-piperidin-4-yl]-3-methyl-1,3- 399 dihydro-benzoimidazol-2-one 240 1-Methyl-3-[1-(4-nitro-benzyl)-piperidin-4-yl]-1,3- 366 dihydro-benzoimidazol-2-one 241 1-Methyl-3-(1-naphthalen-2-ylmethyl-piperidin-4- 371 yl)-1,3-dihydro-benzoimidazol-2-one 242 1-[1-(4-Methanesulfonyl-benzyl)-piperidin-4-yl]-3- 399 methyl-1,3-dihydro-benzoimidazol-2-one 243 1-Methyl-3-[1-(3-nitro-benzyl)-piperidin-4-yl]-1,3- 366 dihydro-benzoimidazol-2-one 244 1-[1-(4-Methanesulfonyl-benzyl)-piperidin-4-yl]-3- 322 methyl-1,3-dihydro-benzoimidazol-2-one 245 4-(2-Methylamino-benzoimidazol-1-yl)-piperidine- 330 1-carboxylic acid tert-butyl ester 246 4-(2-Propylamino-benzoimidazol-1-yl)-piperidine- 358 1-carboxylic acid tert-butyl ester 247 4-(2-Hexylamino-benzoimidazol-1-yl)-piperidine-1- 400 carboxylic acid tert-butyl ester 248 4-(2-Cyclohexylamino-benzoimidazol-1-yl)- 398 piperidine-1-carboxylic acid tert-butyl ester 249 4-(2-Phenylamino-benzoimidazol-1-yl)-piperidine-1- 392 carboxylic acid tert-butyl ester 250 4-(2-Benzylamino-benzoimidazol-1-yl)-piperidine-1- 406 carboxylic acid tert-butyl ester 251 4-(2-Phenethylamino-benzoimidazol-1-yl)- 420 piperidine-1-carboxylic acid tert-butyl ester 252 4-[2-(3-Trifluoromethyl-phenylamino)- 460 benzoimidazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester 253 4-[2-(Pyridin-3-ylamino)-benzoimidazol-1-yl]- 393 piperidine-1-carboxylic acid tert-butyl ester 254 1-Methyl-3-[1-(tetrahydro-pyran-2-ylmethyl)- 329 piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one 255 1-Methyl-3-(1-pyridin-4-ylmethyl-piperidin-4-yl)- 322 1,3-dihydro-benzoimidazol-2-one 256 (3-Fluoro-phenyl)-[4-(2-methylamino- 352 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 257 (3-Fluoro-phenyl)-[4-(2-propylamino- 380 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 258 (3-Fluoro-phenyl)-[4-(2-hexylamino- 422 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 259 [4-(2-Cyclohexylamino-benzoimidazol-1-yl)- 420 piperidin-1-yl]-(3-fluoro-phenyl)-methanone 260 (3-Fluoro-phenyl)-[4-(2-phenylamino- 414 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 261 [4-(2-Benzylamino-benzoimidazol-1-yl)-piperidin- 428 1-yl]-(3-fluoro-phenyl)-methanone 262 (3-Fluoro-phenyl)-[4-(2-phenethylamino- 442 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 263 (3-Fluoro-phenyl)-{4-[2-(3-trifluoromethyl- 482 phenylamino)-benzoimidazol-1-yl]-piperidin-1-yl}- methanone 264 (3-Fluoro-phenyl)-{4-[2-(pyridin-3-ylamino)- 415 benzoimidazol-1-yl]-piperidin-1-yl}-methanone 265 1-[1-(3-Fluoro-benzoyl)-1,2,3,6-tetrahydro-pyridin- 337 4-yl]-1,3-dihydro-benzoimidazol-2-one 266 [4-(2-Methylamino-benzoimidazol-1-yl)-piperidin- 334 1-yl]-phenyl-methanone 267 Phenyl-[4-(2-propylamino-benzoimidazol-1-yl)- 362 piperidin-1-yl]-methanone 268 [4-(2-Hexylamino-benzoimidazol-1-yl)-piperidin- 404 1-yl]-phenyl-methanone 269 [4-(2-Cyclohexylamino-benzoimidazol-1-yl)- 402 piperidin-1-yl]-phenyl-methanone 270 Phenyl-[4-(2-phenylamino-benzoimidazol-1-yl)- 396 piperidin-1-yl]-methanone 271 [4-(2-Benzylamino-benzoimidazol-1-yl)-piperidin- 410 1-yl]-phenyl-methanone 272 [4-(2-Phenethylamino-benzoimidazol-1-yl)- 424 piperidin-1-yl]-phenyl-methanone 273 Phenyl-{4-[2-(3-trifluoromethyl-phenylamino)- 464 benzoimidazol-1-yl]-piperidin-1-yl}-methanone 274 Phenyl-{4-[2-(pyridin-3-ylamino)-benzoimidazol- 397 1-yl]-piperidin-1-yl}-methanone 275 1-(1-Benzoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1,3- 319 dihydro-benzoimidazol-2-one 276 1-[4-(2-Methylamino-benzoimidazol-1-yl)- 286 piperidin-1-yl]-propan-1-one 277 1-[4-(2-Propylamino-benzoimidazol-1-yl)- 314 piperidin-1-yl]-propan-1-one 278 1-[4-(2-Hexylamino-benzoimidazol-1-yl)-piperidin- 356 1-yl]-propan-1-one 279 1-[4-(2-Cyclohexylamino-benzoimidazol-1-yl)- 354 piperidin-1-yl]-propan-1-one 280 1-[4-(2-Phenylamino-benzoimidazol-1-yl)-piperidin- 348 1-yl]-propan-1-one 281 1-[4-(2-Benzylamino-benzoimidazol-1-yl)-piperidin- 362 1-yl]-propan-1-one 282 1-[4-(2-Phenethylamino-benzoimidazol-1-yl)- 376 piperidin-1-yl]-propan-1-one 283 1-{4-[2-(3-Trifluoromethyl-phenylamino)- 416 benzoimidazol-1-yl]-piperidin-1-yl}-propan-1-one 284 1-{4-[2-(Pyridin-3-ylamino)-benzoimidazol-1-yl]- 349 piperidin-1-yl}-propan-1-one 285 1-(1-Propionyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1,3- 271 dihydro-benzoimidazol-2-one 286 (2-Fluoro-phenyl)-[4-(2-methylamino- 352 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 287 (2-Fluoro-phenyl)-[4-(2-propylamino- 380 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 288 (2-Fluoro-phenyl)-[4-(2-hexylamino-benzoimidazol- 422 1-yl)-piperidin-1-yl]-methanone 289 [4-(2-Cyclohexylamino-benzoimidazol-1-yl)- 420 piperidin-1-yl]-(2-fluoro-phenyl)-methanone 290 (2-Fluoro-phenyl)-[4-(2-phenylamino- 414 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 291 [4-(2-Benzylamino-benzoimidazol-1-yl)-piperidin- 428 1-yl]-(2-fluoro-phenyl)-methanone 292 (2-Fluoro-phenyl)-[4-(2-phenethylamino- 442 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 293 (2-Fluoro-phenyl)-{4-[2-(3-trifluoromethyl- 482 phenylamino)-benzoimidazol-1-yl]-piperidin-1-yl}- methanone 294 (2-Fluoro-phenyl)-{4-[2-(pyridin-3-ylamino)- 415 benzoimidazol-1-yl]-piperidin-1-yl}-methanone 295 1-[1-(2-Fluoro-benzoyl)-1,2,3,6-tetrahydro-pyridin- 337 4-yl]-1,3-dihydro-benzoimidazol-2-one 296 (4-Butyl-phenyl)-[4-(2-methylamino-benzoimidazol- 390 1-yl)-piperidin-1-yl]-methanone 297 (4-Butyl-phenyl)-[4-(2-propylamino-benzoimidazol- 418 1-yl)-piperidin-1-yl]-methanone 298 (4-Butyl-phenyl)-[4-(2-cyclohexylamino- 458 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 299 (4-Butyl-phenyl)-[4-(2-phenylamino-benzoimidazol- 452 1-yl)-piperidin-1-yl]-methanone 300 [4-(2-Benzylamino-benzoimidazol-1-yl)-piperidin- 466 1-yl]-(4-butyl-phenyl)-methanone 301 (4-Butyl-phenyl)-[4-(2-phenethylamino- 480 benzoimidazol-1-yl)-piperidin-1-yl]-methanone 302 (4-Butyl-phenyl)-{4-[2-(3-trifluoromethyl- 520 phenylamino)-benzoimidazol-1-yl]-piperidin-1-yl}- methanone 303 (4-Butyl-phenyl)-{4-[2-(pyridin-3-ylamino)- 453 benzoimidazol-1-yl]-piperidin-1-yl}-methanone 304 1-[1-(Naphthalene-2-sulfonyl)-piperidin-4-yl]-1,3- 407 dihydro-benzoimidazol-2-one 305 [4-(2-Methylamino-benzoimidazol-1-yl)-piperidin- 402 1-yl]-(3-trifluoromethyl-phenyl)-methanone 306 [4-(2-Propylamino-benzoimidazol-1-yl)-piperidin- 430 1-yl]-(3-trifluoromethyl-phenyl)-methanone 307 [4-(2-Hexylamino-benzoimidazol-1-yl)-piperidin- 472 1-yl]-(3-trifluoromethyl-phenyl)-methanone 308 [4-(2-Cyclohexylamino-benzoimidazol-1-yl)- 470 piperidin-1-yl]-(3-trifluoromethylphenyl)-methanone 309 [4-(2-Phenylamino-benzoimidazol-1-yl)-piperidin- 464 1-yl]-(3-trifluoromethyl-phenyl)-methanone 310 [4-(2-Benzylamino-benzoimidazol-1-yl)-piperidin- 478 1-yl]-(3-trifluoromethyl-phenyl)-methanone 311 [4-(2-Phenethylamino-benzoimidazol-1-yl)- 492 piperidin-1-yl]-(3-trifluoromethyl-phenyl)- methanone 312 (3-Trifluoromethyl-phenyl)-{4-[2-(3- 532 trifluoromethyl-phenylamino)-benzoimidazol-1-yl]- piperidin-1-yl}-methanone 313 {4-[2-(Pyridin-3-ylamino)-benzoimidazol-1-yl]- 465 piperidin-1-yl}-(3-trifluoromethyl-phenyl)- methanone 314 1-[1-(3-Trifluoromethyl-benzoyl)-1,2,3,6-tetrahydro- 387 pyridin-4-yl]-1,3-dihydro-benzoimidazol-2-one 315 1-[4-(2-Methylamino-benzoimidazol-1-yl)-piperidin- 360 1-yl]-3-phenyl-propenone 316 3-Phenyl-1-[4-(2-propylamino-benzoimidazol-1-yl)- 388 piperidin-1-yl]-propenone 317 1-[4-(2-Hexylamino-benzoimidazol-1-yl)-piperidin- 430 1-yl]-3-phenyl-propenone 318 1-[4-(2-Cyclohexylamino-benzoimidazol-1-yl)- 428 piperidin-1-yl]-3-phenyl-propenone 319 3-Phenyl-1-[4-(2-phenylamino-benzoimidazol-1-yl)- 422 piperidin-1-yl]-propenone 320 1-[4-(2-Benzylamino-benzoimidazol-1-yl)- 436 piperidin-1-yl]-3-phenyl-propenone 321 1-[4-(2-Phenethylamino-benzoimidazol-1-yl)- 450 piperidin-1-yl]-3-phenyl-propenone 322 3-Phenyl-1-{4-[2-(3-trifluoromethyl-phenylamino)- 490 benzoimidazol-1-yl]-piperidin-1-yl}-propenone 323 3-Phenyl-1-{4-[2-(pyridin-3-ylamino)- 423 benzoimidazol-1-yl]-piperidin-1-yl}-propenone 324 4-Methyl-1-[1-(3-phenyl-acryloyl)-1,2,3,6- 359 tetrahydro-pyridin-4-yl]-1,3-dihydro-benzoimidazol- 2-one 325 [1-(1-Benzenesulfonyl-piperidin-4-yl)-1H- 370 benzoimidazol-2-yl]-methyl-amine 326 [1-(1-Benzenesulfonyl-piperidin-4-yl)-1H- 398 benzoimidazol-2-yl]-propyl-amine 327 [1-(1-Benzenesulfonyl-piperidin-4-yl)-1H- 440 benzoimidazol-2-yl]-hexyl-amine 328 [1-(1-Benzenesulfonyl-piperidin-4-yl)-1H- 438 benzoimidazol-2-yl]-cyclohexyl-amine 329 [1-(1-Benzenesulfonyl-piperidin-4-yl)-1H- 432 benzoimidazol-2-yl]-phenyl-amine 330 [1-(1-Benzenesulfonyl-piperidin-4-yl)-1H- 446 benzoimidazol-2-yl]-benzyl-amine 331 [1-(1-Benzenesulfonyl-piperidin-4-yl)-1H- 460 benzoimidazol-2-yl]-phenethyl-amine 332 [1-(1-Benzenesulfonyl-piperidin-4-yl)-1H- 500 benzoimidazol-2-yl]-(3-trifluoromethyl-phenyl)- amine 333 [1-(1-Benzenesulfonyl-piperidin-4-yl)-1H- 433 benzoimidazol-2-yl]-pyridin-3-yl-amine 334 1-(1-Benzenesulfonyl-1,2,3,6-tetrahydro-pyridin- 355 4-yl)-1,3-dihydro-benzoimidazol-2-one 335 1-[1-(5-Dimethylamino-naphthalene-1-sulfonyl)- 450 piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one 343 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)- 386 piperidine-1-sulfonic acid benzylamide 344 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)- 404 piperidine-1-sulfonic acid 4-fluoro-benzylamide 345 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)- 354 piperidine-1-sulfonic acid (2-methoxy-ethyl)-amide 346 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)- 336 piperidine-1-sulfonic acid allylamide

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to included within the spirit and purview of this application and are considered within the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. 

1. A compound having the formula:

in which R¹ is

wherein R² is a member selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R⁶ is selected from substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroarylalkyl; X is a member selected from O and S; and the dashed bond marked a is either a single or a double bond; R¹² is a member independently selected from hydrogen, halo, amino, hydroxy, cyano, nitro, acyl, alkoxy, unsubstituted alkyl,unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroalkyl.
 2. The compound according to claim 1, wherein X is O.
 3. The compound of claim 2, wherein each R¹² is hydrogen.
 4. The compound of claim 2, wherein R² is 4-butyl-phenyl.
 5. The compound of claim 2, wherein R⁶ unsubstituted arylalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroarylalkyl.
 6. The compound of claim 2, wherein R⁶ is a substituted or unsubstituted arylalkyl.
 7. The compound of claim 2, wherein R⁶ is substituted or unsubstituted heteroarylalkyl.
 8. The compound of claim 2, wherein R⁶ is unsubstituted heterocycloalkyl.
 9. The compound of claim 2, wherein R⁶ is a substituted or unsubstituted benzyl.
 10. The compound of claim 2, wherein the dashed bond marked a is a double bond.
 11. The compound of claim 2, wherein the dashed bond marked a is a single bond.
 12. The compound of claim 3, wherein R⁶ is unsubstituted arylalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroarylalkyl.
 13. The compound of claim 2, wherein R² is unsubstituted aryl or unsubstituted heteroaryl.
 14. The compound of claim 12, wherein R² is unsubstituted aryl or unsubstituted heteroaryl.
 15. A composition comprising a pharmaceutically acceptable excipient and the compound of claim
 1. 16. A composition comprising a pharmaceutically acceptable excipient and the compound of claim
 2. 17. A composition comprising a pharmaceutically acceptable excipient and the compound of claim
 3. 18. A composition comprising a pharmaceutically acceptable excipient and the compound of claim
 12. 19. A composition comprising a pharmaceutically acceptable excipient and the compound of claim
 13. 20. A composition comprising a pharmaceutically acceptable excipient and the compound of claim
 14. 21. A composition of claim 15 in unit dose format.
 22. A composition of claim 16 in unit dose format. 